1. Field of the Invention
The present invention concerns improved formulations for transmucosal vaginal delivery of bisphosphonates. In particular, the invention concerns an improved formulation comprising from about 0.01 to about 3200 mg of a selected bisphosphonate, from about 0.01 to about 5% of hydroxypropyl methylcellulose, from about 40 to about 95% of a saturated monoglyceride, diglyceride or triglyceride of fatty acids of length from 8 to 18 carbons or a mixture thereof, from about 5 to about 25% of ethoxydiglycol and, optionally, other pharmaceutically acceptable excipients and additives. The improved transmucosal vaginal formulation delivers more than 60 times more bisphosphonates than can be delivered orally.
The invention further concerns transmucosal devices incorporated with the improved transmucosal vaginal bisphosphonate formulation suitable for use in a method for treatment of osteoporosis, Paget's disease, nonmetastatic neoplastic disease, metastatic cancer of bone, and other related diseases of bone and skeleton and for prevention of bone breakdown, loss of bone mass and strength. The method for treatment of said diseases comprises a step of delivering the improved transmucosal vaginal formulation to the vagina for delivery of bisphosphonates to the systemic circulation.
2. Background and Related Art
Osteoporosis and therewith associated loss of bone mass and strength leading to bone breakdown and fractures is a major medical problem in postmenopausal women.
A number of approaches for prevention of osteoporosis in this patient group have been proposed. These approaches include the administration of high doses of calcium and vitamin D in conjunction with the administration of estrogens, as well as the administration of synthetic substances which bind to estrogen receptors such as raloxifen, tamoxifen, etc.
One of the newer investigated approaches for prevention of osteoporosis is the administration of bisphosphonates. Bisphosphonates were found to prevent bone resorption leading to reduction of bone fractures, especially the fractures of spine and hip. Recent studies have demonstrated that these compounds prevent the loss of bone and enhance bone density in the postmenopausal female population and in patients with Paget's disease of bone (Journal of Clinical Endocrinology and Metabolism, 82(1):265-274 (1997); Journal of Bone and Mineral Research, 12(10):1700-1707 (1997); American Journal of Medicine, 106(5):513-520 (1997); Journal of Clinical Endocrinology and Metabolism, 83(2):396-402 (1998)).
Cumulatively, the above references show that bisphosphonates prevent a breakdown of bone, strengthen bone, increase a bone mass and markedly reduce fractures.
The bisphosphonates were additionally investigated for treatment of cancer, as described, for example, in New England Journal of Medicine, 335:1785-1791 (1996) which reports a decreased frequency of skeletal events in patients with multiple myeloma involving bone and breast cancer with osteolytic metastases following a treatment with bisphosphonates. Clinical trials described in New England Journal of Medicine, 339:398-400 (1998) have shown that adjunctive treatment with bisphosphonates reduces the incidence and number of new bone and visceral metastases in women with high risk, primary breast cancer.
Numerous bisphosphonates are now available for therapeutical use, however, their administration and delivery remains problematic.
A most preferred mode of drug delivery for any drug is, of course, the oral administration. However, this mode of administration of bisphosphonates is limited by the low gastrointestinal absorption and by overall low gastrointestinal tolerability of bisphoshonates. Gastrointestinal absorption of the bisphosphonates is very poor and, typically, only about 1% or less of the administered dose is absorbed into the general circulation.
Additionally, a significant number of women treated with oral bisphosphonates were reported to develop irritation of esophageal mucosa, esophageal reflux and esophagitis (Digestive Diseases and Sciences, 43 (9):1998-2002 (1998); Digestive Diseases and Sciences, 43(5):1009-1015 (1998)). To lessen these undesirable adverse reactions, the oral administration of bisphosphonates requires a very strict regimen which is hard to follow. A noncompliance with this regimen leads to a failure of the treatment.
A primary problem connected with oral administration of bisphosphonates, however, is the inefficiency of the oral delivery because only less than 1% of bisphosphonates is absorbed following the oral administration (Drugs, 53(3):415-434 (1997).
In view of the problems encountered with oral administration of bisphosphonates which limits their utility, it is clear that new delivery mechanisms which would enhance the absorption and bioavailability of these drugs and yet avoid a need for intravenous administration would be extremely advantageous for achieving and increasing a therapeutic potential of bisphosphonates.
U.S. patent application Ser. No. 09/626,025, filed on Jul. 27, 2000, allowed, describes a transmucosal vaginal composition which improves delivery of bisphosphonates by 10 to 30 times compared to the oral delivery. However, the efficacy of that composition is still rather low and thus any further improvement in the efficacy of the bisphosphonate delivery would be an important practical and economic achievement.
It is, therefore, an objective of the present invention to provide an improved formulation for transmucosal vaginal delivery of bisphosphonates suitable to be administered directly to the vagina or incorporated into an appropriate vaginal device as well as methods using such formulation for treatment of osteoporosis, Paget's disease and other related diseases of bone and skeleton or for treating and prevention of cancer, which formulation would enable delivery of larger amounts of bisphosphonates to the general circulation than those delivered orally or with prior formulations.
All references, patents and patent applications cited herein are hereby incorporated by reference in their entirety.